(1) Related Inventions
This application is a continuation-in-part of copending and commonly owned application Ser. No. 07/213,920 filed June 30, 1988 now abandoned, the entire contents of which is expressly incorporated herein by reference.
(2) Field of the Invention
This invention relates to ionic forms of dressings to which a variety of ionic, physiologically- and/or biologically- active materials can be adsorbed so that a controlled release of that material into body exudates of wounds can take place. This invention also relates to methods and systems for preparing a derivatized substrate having ionic groups therein for the preparation of such wound or burn dressings.
(3) Description of the Prior Art
When drugs are systemically administered to treat wounds (including cuts, abrasions, incisions, ulcers and infected wounds or burns), a large portion of the drugs is either degraded or adsorbed by nontarget tissues and only a small portion of the initial dose reaches the target site. The efficiency of systemic dosing is further decreased in the trauma patient (as in accidents, earthquakes, fires and wars) who often suffer a decreased vascular flow and thus have reduced drug circulation. Furthermore, the trauma patient often fails to provide information regarding sensitivity to drugs, or fails to take drugs orally. Topical drug administration, in theory, would provide immediate, direct, and sustained effects at the target site, and reduce side-effects and degradation of drugs encountered in systemic dosing. Topical application also permits rapid removal and replacement of drugs when adverse effects are noticed. When cleansing is not readily available, topical application is more effective in destroying microbial spores because a higher concentration of drugs can be applied. Thus, treatment of wounds or burns will benefit from an improvement of topical administration, whether used alone or in conjunction with systemic dosing.
Currently, antibiotics, e.g. fusidic acid, chlorohexidine, Neomycin, Polymyxin and Bacitracin are topically applied in gel, cream or ointment forms (occasionally in aerosol and powder). Because a high concentration of the drugs are in direct contact with the target tissue, some of the drugs cause allergic reaction by contact with the target tissue, some of drugs cause allergic dermatitis, particularly in patients with stasis ulcers or eczema, or exhibit toxicity.
The art is replete with patents involving the more absorption without ionic bonding of drugs on carriers. Thus, Canadian Patent No. 486,203 to Johnson & Johnson taught the use of gauze, as a carrier, Canadian Patent No. 503,389 to Casumano taught the use of gauze pads, as a carrier, and Canadian Patent No. 823,628 to Wyant used paper toweling as a carrier.
Canadian Patent No. 547,091 to Lerner used materials, e.g. aluminum foil, regenerated cellulose sheets or impervious, grease-proof glassine paper, which have non-capillary faces as carriers.
Canadian Patent No. 588,169 to Chicopee used non-woven fabrics, optionally bonded with internally-plasticized polyvinyl acetates.
Canadian Patent No. 839,229 to Astra used sheets of water-soluble, film-forming compounds.
Canadian Patent No. 1,049,407 to Pharmacia used water-insoluble, hydrophilic macromolecular materials.
U.S. Pat. No. 2,381,621 patented Aug. 7, 1945 by Wallace & Teirnan Products, Inc. taught a therapeutic article including a base material comprising a thin, pliable, hydrophilic, non-porous but water-penetrable material in film form and a plurality of water-soluble medicinal substances distributed by being absorbed but not ionically bound to the base material.
U.S. Pat. No. 2,804,425 patented Aug. 27, 1957 by American Cyanamid Company taught a sterile, anhydrous, storage-stable chlortetracycline-containing wound packing comprising a lintless, heavy-metal-free gauze impregnated with, but not ionically-bonded to, chlortetracycline.
U.S. Pat. No. 3,817,702 patented June 18, 1974 by Bayer Aktiengessellschaft taught an antimicrobial textile material comprising a textile material containing reactive hydrogen sites, e.g. cotton treated with a reagent to introduce anion-active sites, which was then chemically reacted with a biocide to form a salt of the biocide with the textile material. The textile material thus became anion-active, and was finished by treatment with a cation-active microbiocide the ionic bond being so strong as to provide a lastingly, partially anion-active textile material.
U.S. Pat. No. 3,987,793 patented Oct. 26, 1976 by Ethicon Inc. provided a surgical suture which was coated with a ionically-bonded, block elastomeric copolymer so that it was receptive to treatment with antimicrobial compounds the bonding between the copolymer and the antimicrobial compound being so strong as to produce a substance having long-lasting antimicrobial properties.
U.S. Pat. No. 4,549,011 patented Oct. 22, 1985 by Orgenics Ltd. provided a sheet of cellulose or plastic material which was activated with a compound which can covalently bind a liquid thereto, and then a ligand is then coated on the sheet. The ligand is one having an affinity for a substance to be separated from a mixture of substances.
U.S. Pat. No. 4,585,652 patented Apr. 29, 1986 by Regents of the University of Minnesota provided a controlled drug release system comprising a polymer which, in its ionic state, was loaded with bioactive counterions. When the polymer was neutralized the counterions were released into the surrounding medium. The patentee used an electrode comprising a polymer which changed its ionic state for loading and for discharging purposes. This was an unnecessarily complicated system and did not have practicability for general use.
U.K. Patent Application GB 2007096 A published 16th of May, 1979 provided an indicator to show when an antimicrobial composition, which was impregnated in, but not ionically bonded to, a cloth was no longer present in the cloth. The antimicrobial composition was ionically-bonded to a dye, so that when the antimicrobial composition was exhausted from the cloth, the dye also was exhausted, and so no color remained.
To provide a controlled release of drugs, a U.S. Army medical team had developed microcapsules (diameters of &lt;10 .mu.) containing ampicillin for topical application to wound sites. However, these delivery systems (gel, cream, ointment, powder and microcapsule) suffer a practical problem: their even application or removal to and from the target site requires gentle manipulation and is too time-consuming for treatment of a large number of trauma patients in emergency cases.
To overcome this problem, gauze dressings impregnated with a suspension of antibiotics (e.g., fusidic acid and Neomycin) in appropriate media (e.g., petroleum jelly and lanolin) had also been developed. However, such delivery system did not control the release of drugs and thus did not solve the allergy or toxicity problems. Furthermore, the dressings impregnated with gel or liquid did not adsorb the exudate, and may not have provided sufficient breathability which would be desired for the treatment.
Enzymes, e.g. fibrinolytic proteases and deoxyribonucleases, have occasionally been used to dissolve fibrous or purulent accumulations in infected wounds or burns. These enzymes are currently applied in the form of gels (e.g., carboxymethyl cellulose gel) or ointments. Such systems would suffer the same problems of allergy and time-consuming application described above. Furthermore, they did not provide mechanisms for removal of enzymic hydrolysates which are potential irritants.
Apparatus for the treatment of textiles with aqueous solutions of treating agents are also well-known in the art. For example, U.S. Pat. No. 3,910,230, patented Oct. 7, 1975, by H. L. Mercer, provided an apparatus for applying a desired percentage by weight of liquid to a running textile fabric.
U.S. Pat. No. 2,426,668, patented Jan. 27, 1981, by W. Spillmann et al, provided apparatus and methods for the treatment of a web or a number of webs of material guided side by side in the nip between treatment rollers, the web or webs of material being impregnated with or containing treating agents.
U.S. Pat. No. 3,817,702,patented June 18, 1974, by Bayer Aktiengesellschaft provide a laboratory-scale procedure for preparing textile materials lastingly protected from staining by damp and mildew and from rotting by a cation-active microbial. The process taught involved impregnated the fabric, squeezing off the excess, and then drying the fabric. The cation-active microbial was then absorbed by the fabric from an aqueous solution. The excess was squeezed off and unfixed portions of the active compound was washed away.
Some currently-available, commercially-usable processes for the preparation of diethylaminoethyl cellulose (DEAE) and carboxymethyl cellulose (CM) derivatives are directed to modifying fibres or beads of polyhydroxy polymers and often require stirring and heating for relatively long periods of time. For example, U.S. Pat. No. 3,359,258, patented Dec. 19, 1967, by B. A. Toms, provided a commercially-usable process for preparing DEAE by first reacting alkali cellulose and aminoethyl hydrogen sulphate to form aminoethyl cellulose and then further reacting this product with dimethyl sulphate in the presence of an acid binder. In the process taught, a sheet of pulp was impregnated with aminoethyl hydrogen sulfate in a tray. The damp sheet was removed from the tray and then heated, either intact or after shredding. The impregnated pulp, whether in the form of sheet or crumb, was dried and baked under controlled conditions, e.g., at a temperature of about 105.degree. C., for about 2-4 hours. The so-dried sheet or crumb was then coarsely crumbled and dried in air at about 110.degree. C.
Other currently available commercially-usable processes have been developed which involved treating cellulose fabrics in the same way. For example, U.S. Pat. No. 3,567,358, patented Mar. 2, 1971, by D. M. Soignet et al, provided cellulose fabrics which were diethylaminoethylated and/or carboxymethylated and thereafter were heated at elevated temperatures under vacuum for extended periods of time to form cross-links.
U.S. Pat. No. 3,918,899, patented Nov. 11, 1975, by D. M. Perrier et al, provided, as textiles, CM-celluloses, e.g., CM-cottons, prepared in aqueous media.
U.S. Pat. No. 3,997,647, patented Dec. 14, 1976, by F. O. Lassen, provided filaments of chemically-modified cellulose fibres and webs constructed from such filaments.
The synthesis and characterization of DEAE and CM derivatives of polysaccharides, e.g. cellulose, dextran and starch, are well-documented. The derivatives are non-toxic, non-allergenic and have been used as food additives or pharmaceuticals. Although these derivatives are provided in fiber, powder or granular forms, cloth forms of the derivatives are not commercially available. The cloth forms have definite advantages in large-scale purification and immobilization of ionic macromolecules (e.g., enzymes) because they provide easy handling (washing, transfer and removal) and faster flow in a packed bed operation. High degrees of derivatization of the cotton cloth tend either to stiffen the fabric texture, or to reduce the fabric strength. Furthermore, the edges of the woven fabric tend to ravel after modification. Cotton surgical dressing or gauze suffer even greater textural changes.
Currently available methods for DEAE and CM derivatization are aimed for modifying fibers or beads of polyhydroxy polymers and often require stirring and heating for relatively short periods of time. Since efficient stirring and rapid heating are difficult for modification of these fabrics in large sizes and quantities, processes have been devised by the present applicants as will be more fully described hereinafter which allow modification without stirring and at near ambient temperatures.